tbuckley/cabot-search huggingface dataset:
Hepatocyte‐derived MASP1‐enriched small extracellular vesicles activate HSCs to promote liver fibrosis
Authors: Xianzhi Liu, Siwei Tan, Huiling Liu, Jie Jiang, Xing Wang, Leijia Li, Bin Wu
Journal: Hepatology (2022)

Liver fibrosis is a chronic disease characterized by different etiological agents; dysregulated interactions between hepatocytes and HSCs contribute to this disease. β-arrestin 1 (ARRB1) plays an important role in liver fibrosis; however, the effect of ARRB1 on the crosstalk between hepatocytes and HSCs in liver fibrosis is unknown. The aim of this study is to investigate how ARRB1 modulates hepatocyte and HSC activation during liver fibrosis.Normal and fibrotic human liver and serum samples were obtained. CCl 4 -induced liver fibrosis and methionine-choline deficiency-induced NASH models were constructed. Primary hepatocytes and HSCs were isolated, and human hepatic LO2 and stellate LX2 cells were used. Small extracellular vesicles (EVs) were purified, and key proteins were identified. ARRB1 was up-regulated in hepatocytes and associated with autophagic blockage in liver fibrosis. ARRB1 increased the release of hepatocyte-derived small EVs by inhibiting multivesicular body lysosomal degradation and activating Rab27A, thereby activating HSCs. Proteomic analyses showed that mannan-binding lectin serine protease 1 (MASP1) was enriched in hepatocyte-derived small EVs and activated HSCs via p38 mitogen-activated protein kinase (MAPK)/activating transcription factor 2 (ATF2) signaling. ARRB1 up-regulated MASP1 expression in hepatocytes. MASP1 promoted liver fibrosis in mice. Clinically, MASP1 expression was increased in the serum and liver tissue of patients with liver fibrosis.ARRB1 up-regulates the release of hepatocyte-derived MASP1-enriched small EVs by regulating the autophagic-lysosomal/multivesicular body pathway and Rab27A. Hepatocyte-derived MASP1 activates HSCs to promote liver fibrogenesis through p38 MAPK/ATF2 signaling. Thus, MASP1 is a pivotal therapeutic target in liver fibrosis.
Author Correction: Neoadjuvant clinical trials provide a window of opportunity for cancer drug discovery
Authors: Thomas U. Marron, Matthew D. Galsky, Bachir Taouli, Maria Isabel Fiel, Stephen Ward, Edward Kim, David Yankelevitz, Deborah Doroshow, Emma Guttman-Yassky, Benjamin Ungar, Saurabh Mehandru, Benjamin J. Golas, Daniel Labow, John Sfakianos, Sujit S. Nair, Dimple Chakravarty, Michael Buckstein, Xiaoyu Song, Effi Kenigsberg, Sacha Gnjatic, Brian D. Brown, Joseph Sparano, Ashutosh Tewari, Myron Schwartz, Nina Bhardwaj, Miriam Merad
Journal: Nature Medicine (2022)
Antitumor CAR T-cell Screening Platform: Many Are Called, but Few Are Chosen
Authors: Olivier Adotévi, Jeanne Galaine
Journal: Cancer Research (2022)

Abstract Treatment with T cells expressing chimeric antigen receptors (CAR) is a promising anticancer therapy. However, this approach has several limitations and has not yet been effectively applied to treat solid tumors. The study by Panowski and colleagues represents the first comparative analysis of multiple single chain fragment variable (scFv)-based anti-CD70 CAR T-cell clones for the development of a clinical product to treat renal cell carcinoma (RCC). Despite the risk of T-cell fratricide due to CD70 expression on T cells, CD70 CAR T cells were produced successfully thanks to the protective CD70 masking phenomenon. Two distinct classes of CAR T cells were identified with different memory phenotypes, activation statuses, and cytotoxic activity. CD70 CAR T cells presented high cytotoxic activity against RCC both in vitro in RCC cell lines and in vivo in patient-derived xenograft mouse models. The off-target effects expected on the lymphoid compartment were confirmed by tissue cross-reactivity staining and in a cynomolgus monkey preclinical model with CD3-CD70 bispecific antibody treatment. The efficacy and the toxicity profile of the lead CD70 CAR T-cell candidate instigated the researchers to proceed with upscaled clinical production. This article emphasizes the influence of the scFv of the CARs on their efficacy:toxicity balance. Ultimately, they successfully managed to develop a highly effective CAR T-cell candidate to treat a solid tumor by an allogeneic approach, thereby overcoming two major hurdles to broaden application of CAR T-cell therapy. See related article by Panowski et al., p. 2610
Preinvasive to Invasive: PD-1–Expressing Macrophages Shift Lung Cancer into High Gear
Authors: Juyeun Lee, Defne Bayik, Justin D. Lathia
Journal: Cancer Research (2022)

Abstract Lung adenocarcinoma is the most common subtype of lung cancer, which has the second highest incidence among cancers. Immunotherapy has revolutionized lung cancer treatment, yet the checkpoint blockade response rate is less than 20% in patients with lung adenocarcinoma. As lung adenocarcinoma consists of heterogeneous histologic subsets with diverse tumor invasion phenotypes and clinical outcomes, understanding the mechanisms of resistance based on the histology subset is essential. In the current issue, Jang and colleagues demonstrated that PD-1–expressing macrophages are the dominant immune cell population in the tumor-immune microenvironment (TiME) of invasive lung adenocarcinoma and are responsible for driving tumor progression from preinvasive to invasive subtypes. PD-1–expressing macrophages are protumorigenic and highly plastic, potentially promoting invasive solid tumor development. Ablation of macrophages remodels the TiME and leads to a favorable anti-PD-1 blockade response, suggesting a potential combination therapy in patients with lung adenocarcinoma resistant to monotherapy. This current work highlights the spatiotemporal dynamics of the TiME during lung adenocarcinoma progression and the critical role of PD-1–expressing macrophages in driving tumorigenesis as well as resistance to immunotherapy. See related article by Jang et al., p. 2593
Dynamic prediction of mortality after traumatic brain injury using a machine learning algorithm
Authors: Rahul Raj, Jenni M. Wennervirta, Jonathan Tjerkaski, Teemu M. Luoto, Jussi P. Posti, David W. Nelson, Riikka Takala, Stepani Bendel, Eric P. Thelin, Teemu Luostarinen, Miikka Korja
Journal: npj Digital Medicine (2022)

Intensive care for patients with traumatic brain injury (TBI) aims to optimize intracranial pressure (ICP) and cerebral perfusion pressure (CPP). The transformation of ICP and CPP time-series data into a dynamic prediction model could aid clinicians to make more data-driven treatment decisions. We retrained and externally validated a machine learning model to dynamically predict the risk of mortality in patients with TBI. Retraining was done in 686 patients with 62,000 h of data and validation was done in two international cohorts including 638 patients with 60,000 h of data. The area under the receiver operating characteristic curve increased with time to 0.79 and 0.73 and the precision recall curve increased with time to 0.57 and 0.64 in the Swedish and American validation cohorts, respectively. The rate of false positives decreased to ≤2.5%. The algorithm provides dynamic mortality predictions during intensive care that improved with increasing data and may have a role as a clinical decision support tool.
Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management
Authors: Ping Jin, Jingwen Jiang, Li Zhou, Zhao Huang, Edouard C. Nice, Canhua Huang, Li Fu
Journal: Journal of Hematology & Oncology (2022)

Drug resistance represents a major obstacle in cancer management, and the mechanisms underlying stress adaptation of cancer cells in response to therapy-induced hostile environment are largely unknown. As the central organelle for cellular energy supply, mitochondria can rapidly undergo dynamic changes and integrate cellular signaling pathways to provide bioenergetic and biosynthetic flexibility for cancer cells, which contributes to multiple aspects of tumor characteristics, including drug resistance. Therefore, targeting mitochondria for cancer therapy and overcoming drug resistance has attracted increasing attention for various types of cancer. Multiple mitochondrial adaptation processes, including mitochondrial dynamics, mitochondrial metabolism, and mitochondrial apoptotic regulatory machinery, have been demonstrated to be potential targets. However, recent increasing insights into mitochondria have revealed the complexity of mitochondrial structure and functions, the elusive functions of mitochondria in tumor biology, and the targeting inaccessibility of mitochondria, which have posed challenges for the clinical application of mitochondrial-based cancer therapeutic strategies. Therefore, discovery of both novel mitochondria-targeting agents and innovative mitochondria-targeting approaches is urgently required. Here, we review the most recent literature to summarize the molecular mechanisms underlying mitochondrial stress adaptation and their intricate connection with cancer drug resistance. In addition, an overview of the emerging strategies to target mitochondria for effectively overcoming chemoresistance is highlighted, with an emphasis on drug repositioning and mitochondrial drug delivery approaches, which may accelerate the application of mitochondria-targeting compounds for cancer therapy.
The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress glioblastoma progression
Authors: Ye Yuan, Li‐Hong Wang, Xian‐Xian Zhao, Jiao Wang, Meng‐Si Zhang, Qing‐Hua Ma, Sen Wei, Ze‐Xuan Yan, Yue Cheng, Xiao‐Qing Chen, Hong‐Bo Zou, Jia Ge, Yan Wang, Xia Zhang, You‐Hong Cui, Tao Luo, Xiu‐Wu Bian
Journal: Cancer Communications (2022)

Abstract Background Elucidation of the post‐transcriptional modification has led to novel strategies to treat intractable tumors, especially glioblastoma (GBM). The ubiquitin‐proteasome system (UPS) mediates a reversible, stringent and stepwise post‐translational modification which is closely associated with malignant processes of GBM. To this end, developing novel therapeutic approaches to target the UPS may contribute to the treatment of this disease. This study aimed to screen the vital and aberrantly regulated component of the UPS in GBM. Based on the molecular identification, functional characterization, and mechanism investigation, we sought to elaborate a novel therapeutic strategy to target this vital factor to combat GBM. Methods We combined glioma datasets and human patient samples to screen and identify aberrantly regulated E3 ubiquitin ligase. Multidimensional database analysis and molecular and functional experiments in vivo and in vitro were used to evaluate the roles of HECT, UBA and WWE domain‐containing E3 ubiquitin ligase 1 (HUWE1) in GBM. dCas9 synergistic activation mediator system and recombinant adeno‐associated virus (rAAV) were used to endogenously overexpress full‐length HUWE1 in vitro and in glioma orthotopic xenografts. Results Low expression of HUWE1 was closely associated with worse prognosis of GBM patients. The ubiquitination and subsequent degradation of N‐Myc mediated by HUWE1, leading to the inactivation of downstream Delta‐like 1 (DLL1)‐NOTCH1 signaling pathways, inhibited the proliferation, invasion, and migration of GBM cells in vitro and in vivo. A rAAV dual‐vector system for packaging and delivery of dCas9‐VP64 was used to augment endogenous HUWE1 expression in vivo and showed an antitumor activity in glioma orthotopic xenografts. Conclusions The E3 ubiquitin ligase HUWE1 acts through the N‐Myc‐DLL1‐NOTCH1 signaling axis to suppress GBM progression. Antitumor activity of rAAV dual‐vector delivering dCas9‐HUWE1 system uncovers a promising therapeutic strategy for GBM.
Transcriptional Circuitry of NKX2-1 and SOX1 Defines an Unrecognized Lineage Subtype of Small-Cell Lung Cancer
Authors: Ranran Kong, Ayushi S. Patel, Takashi Sato, Feng Jiang, Seungyeul Yoo, Li Bao, Abhilasha Sinha, Yang Tian, Maya Fridrikh, Shuhui Liu, Jie Feng, Xijing He, Jiantao Jiang, Yuefeng Ma, Karina Grullon, Dawei Yang, Charles A. Powell, Mary Beth Beasley, Jun Zhu, Eric L. Snyder, Shaomin Li, Hideo Watanabe
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: The current molecular classification of small-cell lung cancer (SCLC) on the basis of the expression of four lineage transcription factors still leaves its major subtype SCLC-A as a heterogeneous group, necessitating more precise characterization of lineage subclasses. Objectives: To refine the current SCLC classification with epigenomic profiles and to identify features of the redefined SCLC subtypes. Methods: We performed unsupervised clustering of epigenomic profiles on 25 SCLC cell lines. Functional significance of NKX2-1 (NK2 homeobox 1) was evaluated by cell growth, apoptosis, and xenograft using clustered regularly interspaced short palindromic repeats–Cas9 (CRISPR-associated protein 9)–mediated deletion. NKX2-1–specific cistromic profiles were determined using chromatin immunoprecipitation followed by sequencing, and its functional transcriptional partners were determined using coimmunoprecipitation followed by mass spectrometry. Rb1flox/flox; Trp53flox/flox and Rb1flox/flox; Trp53flox/flox; Nkx2-1flox/flox mouse models were engineered to explore the function of Nkx2-1 in SCLC tumorigenesis. Epigenomic landscapes of six human SCLC specimens and 20 tumors from two mouse models were characterized. Measurements and Main Results: We identified two epigenomic subclusters of the major SCLC-A subtype: SCLC-Aα and SCLC-Aσ. SCLC-Aα was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found that NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-Aα. In addition, we found that maintenance of this neural identity in SCLC-Aα is mediated by collaborative transcriptional activity with another neuronal transcriptional factor, SOX1 (SRY-box transcription factor 1). Conclusions: We comprehensively describe additional epigenomic heterogeneity of the major SCLC-A subtype and define the SCLC-Aα subtype by the core regulatory circuitry of NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain neuronal linage state.
Adipose lipolysis is important for ethanol to induce fatty liver in the National Institute on Alcohol Abuse and Alcoholism murine model of chronic and binge ethanol feeding
Authors: Mallika Mathur, Yu‐Te Yeh, Rakesh K. Arya, Long Jiang, Majid Pornour, Weiping Chen, Yinyan Ma, Bin Gao, Ling He, Zhekang Ying, Bingzhong Xue, Hang Shi, Youngshim Choi, Liqing Yu
Journal: Hepatology (2022)

Alcohol-associated liver disease (ALD) pathologies include steatosis, inflammation, and injury, which may progress to fibrosis, cirrhosis, and cancer. The liver receives ~60% of fatty acids from adipose tissue triglyceride hydrolysis, but the role of this lipolytic pathway in ALD development has not been directly examined in any genetic animal models with selective inactivation of adipose lipolysis.
Impact of vaping on respiratory health
Authors: Andrea Jonas
Journal: BMJ (2022)

Widespread uptake of vaping has signaled a sea change in the future of nicotine consumption. Vaping has grown in popularity over the past decade, in part propelled by innovations in vape pen design and nicotine flavoring. Teens and young adults have seen the biggest uptake in use of vape pens, which have superseded conventional cigarettes as the preferred modality of nicotine consumption. Relatively little is known, however, about the potential effects of chronic vaping on the respiratory system. Further, the role of vaping as a tool of smoking cessation and tobacco harm reduction remains controversial. The 2019 E-cigarette or Vaping Use-Associated Lung Injury (EVALI) outbreak highlighted the potential harms of vaping, and the consequences of long term use remain unknown. Here, we review the growing body of literature investigating the impacts of vaping on respiratory health. We review the clinical manifestations of vaping related lung injury, including the EVALI outbreak, as well as the effects of chronic vaping on respiratory health and covid-19 outcomes. We conclude that vaping is not without risk, and that further investigation is required to establish clear public policy guidance and regulation.
Automated video-based assessment of facial bradykinesia in de-novo Parkinson’s disease
Authors: Michal Novotny, Tereza Tykalova, Hana Ruzickova, Evzen Ruzicka, Petr Dusek, Jan Rusz
Journal: npj Digital Medicine (2022)

Even though hypomimia is a hallmark of Parkinson's disease (PD), objective and easily interpretable tools to capture the disruption of spontaneous and deliberate facial movements are lacking. This study aimed to develop a fully automatic video-based hypomimia assessment tool and estimate the prevalence and characteristics of hypomimia in de-novo PD patients with relation to clinical and dopamine transporter imaging markers. For this cross-sectional study, video samples of spontaneous speech were collected from 91 de-novo, drug-naïve PD participants and 75 age and sex-matched healthy controls. Twelve facial markers covering areas of forehead, nose root, eyebrows, eyes, lateral canthal areas, cheeks, mouth, and jaw were used to quantitatively describe facial dynamics. All patients were evaluated using Movement Disorder Society-Unified PD Rating Scale and Dopamine Transporter Single-Photon Emission Computed Tomography. Newly developed automated facial analysis tool enabled high-accuracy discrimination between PD and controls with area under the curve of 0.87. The prevalence of hypomimia in de-novo PD cohort was 57%, mainly associated with dysfunction of mouth and jaw movements, and decreased variability in forehead and nose root wrinkles (p < 0.001). Strongest correlation was found between reduction of lower lip movements and nigro-putaminal dopaminergic loss (r = 0.32, p = 0.002) as well as limb bradykinesia/rigidity scores (r = -0.37 p < 0.001). Hypomimia represents a frequent, early marker of motor impairment in PD that can be robustly assessed via automatic video-based analysis. Our results support an association between striatal dopaminergic deficit and hypomimia in PD.
Highlights from Recent Cancer Literature
Journal: Cancer Research (2022)

ILC1s as Potential Cellular-Based Therapy for AMLType I innate lymphoid cells (ILC1), a population of non-B and non-T lymphocytes emerging from the common lymphoid progenitor, reside primarily in the liver, regulating defenses and inflammatory responses via production of cytokines.While studying the role of ILC1s in cancer, Li and colleagues showed that healthy ILC1s stimulate leukemia stem cell (LSC) apoptosis and divert differentiation of stem cells from acute myeloid leukemia (AML) blasts toward nonleukemic progenitors, while not impacting normal hematopoietic stem cells.This is achieved through the production of IFNg, dependent on cell-cell contact through DNAM-1 and IL7Ra expressed on ILC1s.IFNg-mediated signaling through JAK-STAT and PI3K-AKT is needed for the antileukemic function.Moreover, ILC1s from AML murine models or AML patients have reduced antileukemic activity toward the LSCs.
PARP14 is a novel target in STAT6 mutant follicular lymphoma
Authors: Michael Mentz, William Keay, Carolin Dorothea Strobl, Martina Antoniolli, Louisa Adolph, Michael Heide, Axel Lechner, Sarah Haebe, Elisa Osterode, Robert Kridel, Christoph Ziegenhain, Lucas Esteban Wange, Johannes Adrian Hildebrand, Tanaya Shree, Elisabeth Silkenstedt, Annette M. Staiger, German Ott, Heike Horn, Monika Szczepanowski, Julia Richter, Ronald Levy, Andreas Rosenwald, Wolfgang Enard, Ursula Zimber-Strobl, Michael von Bergwelt-Baildon, Wolfgang Hiddemann, Wolfram Klapper, Marc Schmidt-Supprian, Martina Rudelius, Deepak Bararia, Verena Passerini, Oliver Weigert
Journal: Leukemia (2022)

The variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (TFH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6MUT lymphoma cells and in STAT6MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6MUT but not STAT6WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6MUT FL.
Helen Salisbury: Learning to say no
Authors: Helen Salisbury
Journal: BMJ (2022)

<h3>Objective</h3> Transcatheter aortic valve implantation (TAVI) has become an alternative to surgical aortic valve replacement (sAVR) in selected high risk patients. While improvement in left ventricular function after TAVI has been demonstrated, little is known about the impact on right ventricular (RV) function. Since postoperative RV dysfunction is linked to adverse outcomes, the authors sought to investigate the effect of TAVI and aortic valve replacement (AVR) on RV function using speckle tracking echocardiography. <h3>Design</h3> Cross-sectional study in tertiary healthcare setting. <h3>Setting</h3> 101 patients with severe symptomatic aortic stenosis (age 81±11 yrs) who underwent TAVI and 22 patients who underwent sAVR were included. RV function was assessed using 2D longitudinal strain (RV-LS), fractional area change and tricuspid annular plain systolic excursion before and after sAVR and TAVI (median 89 days). <h3>Results</h3> Although the TAVI group had worse baseline characteristics, RV function remained unchanged in this group whereas significant deterioration of RV function was observed in patients undergoing conventional AVR: RV-LS (−25.2±6.1 vs −20.0±7.0%; p=0.009), RV-fractional area change (47.0±7.0 vs 39.8±10.7%, p=0.019) and tricuspid annular plain systolic excursion (24±5 vs 16±4 mm, p=0.0001). <h3>Conclusion</h3> While TAVI did not affect RV function it deteriorated significantly in patients undergoing sAVR. The authors speculate that this may be related to the detrimental effects of pericardiotomy and, to a lesser degree, cardiopulmonary bypass. While further studies are required to assess the clinical significance of this finding, these data suggest that patients with pre-existing RV dysfunction may benefit from TAVI and that RV function should be incorporated into future risk scores.
<scp>TET2</scp> deficiency exacerbates nasal polypogenesis by inducing epithelial‐to‐mesenchymal transition
Authors: Peiqiang Liu, Danxue Qin, Zhifeng Deng, Xiaoting Tong, Kunyu Liu, Wenjun Fan, Jingyu Huang, Huiqin Zhou, Wanyang Gong, Jing Jin, Hao Lv, Siyuan Chen, Zezhang Tao, Yu Xu
Journal: Allergy (2022)

Appendix S1 Figure S1 Figure S2 Figure S3 Figure S4 Table S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.